Nitrite or sildenafil, but not BAY 41-2272, blunt acute pulmonary embolism-induced increases in circulating matrix metalloproteinase-9 and oxidative stress.

Abstract

INTRODUCTION:

Inhibition of matrix metalloproteinases (MMPs) improves the hemodynamics during acute pulmonary embolism (APE) and oxidative stress upregulates MMPs. We compared the effects of different NO-cGMP pathway activators on APE-induced increases in MMPs.

MATERIALS AND METHODS:

Hemodynamic and biochemical evaluations were performed in non-embolized dogs treated with saline (N=5), and in microspheres embolized dogs receiving saline (n=9), or nitrite (6.75 micromol/kg i.v. over 15 min followed by 0.28 micromol/kg/min; n=5), or sildenafil (0.25 mg/kg; n=5), or BAY 41-2272 (0.03, 0.1, 0.3, and 1 mg/kg/h; n=5). Plasma thiobarbituric acid reactive substances (TBARS) concentrations were determined. Zymograms of plasma samples were performed, and in vitro antioxidant effects or inhibition of MMPs by these drugs were examined.

RESULTS:

APE increased mean pulmonary artery pressure by ~25 mmHg. Nitrite, BAY 41-2272, or sildenafil reversed this increase by ~40% (P<0.05). Similar effects were seen on the pulmonary vascular resistance. While both nitrite and sildenafil produced no systemic effects, the highest dose of BAY 41-2272 produced systemic hypotension (P<0.05). While nitrite and sildenafil blunted the increases in plasma pro-MMP-9 levels and TBARS (all P<0.05), BAY 41-2272 produced no such effects. Nitrite and sildenafil produced in vitro antioxidant effects and inhibited MMPs only at high concentrations. BAY 41-2272 produced no such effects.

CONCLUSIONS:

Activation of the NO-cGMP pathway with nitrite or sildenafil, but not with BAY 41-2272, attenuates APE-induced oxidative stress and increased MMP-9 levels. These findings are consistent with the idea that NO-cGMP pathway activators with antioxidant effects prevent the release of MMP-9 during APE.

• Authors: Carlos A Dias-Junior, Stefany B A Cau, Alisson M Oliveira, Michele M Castro, Marcelo F Montenegro, Raquel F Gerlach, Jose E Tanus-Santos
• Journal: Thrombosis research (Thromb Res) Vol. 124 Issue 3 Pg. 349-55 (Jul 2009) ISSN: 1879-2472 [Electronic] United States
• PMID: 19150571 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
• Matrix Metalloproteinase Inhibitors
• Nitrites
• Phosphodiesterase Inhibitors
• Piperazines
• Purines
• Pyrazoles
• Pyridines
• Sulfones
• Sildenafil Citrate
• Matrix Metalloproteinase 9

Topics

• Acute Disease
• Animals
• Disease Models, Animal
• Dogs
• Female
• Humans
• Male
• Matrix Metalloproteinase 9 (blood)
• Matrix Metalloproteinase Inhibitors
• Nitrites (administration & dosage)
• Oxidative Stress (drug effects)
• Phosphodiesterase Inhibitors (administration & dosage)
• Piperazines (administration & dosage)
• Pulmonary Embolism (drug therapy, enzymology)
• Purines (administration & dosage)
• Pyrazoles (administration & dosage)
• Pyridines (administration & dosage)
• Sildenafil Citrate
• Sulfones (administration & dosage)